HIV-specific CD4 T cell responses, particularly to the envelope glycoproteins, are poor or absent in the majority of HIV-infected subjects. The reason for this specific T cell unresponsiveness remains unclear. One element of the immune response known to have the capacity to modulate specific T cell responses is antibodies (Abs). Abs forming antigen/Ab complexes can alter the uptake, processing, and/or presentation of an antigen, resulting in enhanced or suppressed T cell responses to that antigen. Recently, we showed that CD4 T cell responses to gp120 are inhibited in the presence of serum Abs from HIV+ patients, and specifically by monoclonal Abs (mAbs) to the CD4 binding domain of gp120 (gp120cmbd). Hence, the presence of anti-gp 120CD4bdAbs in the sera of HIV+ individuals may contribute to the poor gp 120-specific T cell responses seen in most infected individuals. The main objective of the proposed study is to investigate the physiological relevance of anti-gp120co4ba Abs. In this study, we will evaluate the suppressive activity of different anti-gp120coabd mAbs that have varying levels of affinity for gp120 (Aim 1). We will compare the levels and activity of anti-gp120coabd Abs in the sera of HIV+ subjects who are able to maintain HIV env-specific Th responses and in the sera of those who lack anti-env Th responses (Aim 2). Since the majority of HIV+ individuals produce anti-gpl20coabd Abs and have no detectable Th responses to env, the absence or low levels of anti-gpl20conbd Abs in unique cohorts of HIV+ subjects with env-specific Th responses would be a first indication of anti-gp120cO4bd Abs influencing env-specific Th responses in vivo. We also will evaluate the kinetics of appearance of anti-gp120Cmbd Abs early after HIV infection and after immunization with candidate HIV vaccines, and determine the relationship between these Abs with changes in Th responses to env (Aim 3). Finally, the suppressive effect of anti-gp120cD4bd Abs will be evaluated in vitro and in vivo using a mouse system, allowing us to examine more directly the physiologic role of these Abs in modulating env-specific Th responses (Aim 4). The proposed study is an essential first step to understanding the pathogenic role of Abs in HIV infection, and will provide important information for the development of more effective AIDS vaccines.